The amyloid of neurodegenerative diseases like Alzheimer's Disease (AD) and related disorders in man is derived by proteolysis of a large membrane precursor protein (APP). Our central interest lies in the apparent link between neurodegeneration and amyloidogenic proteins, and the determination of the factors that initiate and perpetuate amyloid formation. Our working hypothesis is that genetic variant(s) and/or some aberrant posttranslational modification of Alzheimer's APP causes structural/conformational modifications. Proteins thus altered may strongly resist proteolytic attack, and/or they may undergo abnormal degradation. These protease-resistant cleavage peptides with strong tendency to aggregate may bind to other cellular or serum components, thus facilitating polymerization and fibril formation. The most likely pathological cascade for AD, then, is: amyloid deposition, neurofibrillary tangle formation and neuronal death. Better biochemical understanding of this pathological process in human and in animal models would facilitate therapeutic intervention. The Specific Aims of this LEAD award application are: i) The biochemical and immunohistochemical characterization of amyloid proteins and preamyloid lesions from familial and sporadic AD and Hereditary Cerebral Hemorrhage with Amyloidosis, Dutch type (HCHWA-D) (PROJECT 1). ii) The mechanisms of amyloid formation: to study the influence of the known mutations of the APP gene and amyloid associated proteins on fibril formation using synthetic peptides and the 16-19 kDa APP fragments produced by alternative degradation pathways. Therapeutic approaches to inhibit fibrillogenesis will be evaluated in transgenic mice (PROJECT 2). iii) The study of the alternative processing and biological properties of APP (PROJECT 3).. iv) The identification of mutations of the APP gene in families with early onset FAD and the construction of an animal model: transgenic mice harboring the human APP gene with the different mutations (PROJECT 4). v) The characterization of a novel type of familial cerebrovascular amyloidosis with dementia in British patients that is not related to other known types.